Cardiotonic aroylthiazolones

ABSTRACT

Aroylthiazolones enhance myocardial contractile force and are useful as cardiotonics in the treatment of heart failure.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 787,226, filed Oct. 15,1985.

BACKGROUND OF THE INVENTION

This invention relates to the certain aroylthiazolones which enhancemyocardial contractile force and are useful as cardiotonics in thetreatment of heart failure.

Heart failure is that physiological condition resulting from theinability of the ventricular myocardium to maintain adequate blood flowto the peripheral body tissues and includes congestive heart failure,backward and forward heart failure, right ventricular and leftventricular heart failure, and high-output and low-output heart failure.Heart failure can be caused by myocardial ischemia, myocardialinfarction, excessive alcohol usage, pulmonary embolism, infection,anemia, arrhythmias and systemic hypertension. Symptoms includetachycardia, fatigue with exertion, hyspnea, orthopnea and pulmonaryedema.

Treatment involves either removal or correction of the underlying causeor involves control of the heart failure state. Management or controlcan be accomplished by increasing cardiac output or by decreasingcardiac workload. While workload can be reduced by reduction of physicalactivities and physical and emotional rest, increasing cardiac outputhas traditionally involved digitalis therapy. Digitalis stimulatescontractile force of the heart which increases cardiac output andimproves ventricular emptying. In this way digitalis therapy normalizesvenous pressure and reduces peripheral vasoconstriction, circulatorycongestion, and organ hypoperfusion.

Unfortunately, optimal doses of digitalis vary with the patient's age,size and condition and the therapeutic-to-toxic ratio is quite narrow.In most patients the lethal dose is only about five to ten times theminimal effective dose with some toxic effects becoming apparent at only1.5-2 times the effective dose. For those reasons, dose must becarefully tailored to suit the individual and frequent clinicalexaminations and electrocardiograms are necessary to detect early signsof digitalis intoxication. Nevertheless digitalis intoxication isreported in up to one-fifth of hospitalized patients undergoing therapy.The need for less toxic cardiotonic agents is thus readily apparent.

Applicants have discovered certain aroylthiazolones which possess potentcardiotonic activity and by comparison to digitalis have fewer toxiceffects.

SUMMARY OF THE INVENTION

This invention is directed to pharmaceutically active aroylthiazolonesof formula 1 ##STR1## wherein R₁ is a hydrogen or (C₁ -C₄)alkyl group;and

R₂ is an unsubstituted benzyl or a phenyl or benzyl substituted with oneor two members of the group consisting of (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,carboxy, carb(C₁ -C₄)alkoxy, imidazolyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkylsulfonyl, (C₁ -c₄)alkylsulfinyl, trifluoromethyl, cyano, amino,mono and di (C₁ -C₄) alkylamino, pyrolidino, piperidino, morpholino,piperazino N-(C₁ -C₄) alkylpiperazino, and halogen group or amethylenedioxy group.

These compounds enhance myocardial contractile force and are useful ascardiotonics in the treatment of heart failure.

DETAILED DESCRIPTION OF THE INVENTION

The formula 1 compounds exists in two tautomeric forms structurallydepicted in formula 2 ##STR2## wherein R₁ and R₂ are as defined above.Throughout this disclosure, aroylthiazolones of formula 1 are intendedto include the tautomers of formula 2.

The ring nitrogen of the formula 1 compounds can be substituted with a(C₁ -C₄)alkyl group, an alkanoyl group such as an acetyl group, or abenzoyl group. These nitrogen substituted compounds are equivalent tothe unsubstituted compounds primarily because the substituted is clevedupon administration to a patient but also because many of the nitrogensubstituted compounds independently possess significant ability toenhance myocardial contractile force and are useful cardiotonic agents.

As used herein the term (C₁ -C₄)alkyl and the alkyl portion of thealkoxy, carb(C₁ -C₄)alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,mono- and di- alkylamino, and N-substituted piperazino groups means astraight or branched alkyl group of from one to four carbon atoms.Illustrative examples of (C₁ -C₄)alkyl group are methyl, ethyl,isopropyl, butyl, and sec-butyl. The term halogen means a fluoro,chloro, bromo or iodo group.

Preferred compounds of this invention are those compounds of formula 1wherein R₁ is a hydrogen, methyl, or ethyl group. Also preferred arethose formula 1 compounds wherein R₂ a substituted phenyl group. Morepreferred are those compounds of formula 1 wherein R₂ is a phenylsubstituted with an amino or a mono- or di- (C₁ -C₄) alkylamino group.The most preferred compounds of this invention are those compounds offormula 1 wherein R₂ is a dimethylaminophenyl and those compoundswherein R₁ is methyl.

As examples of compounds of formula 1 there can be mentioned thefollowing:

5-(4-cyanobenzoyl)-4-methyl-2(3H)-thiazolone;

4-methyl-5-(4-fluorobenzoyl)-2(3H)-thiazolone;

5-(3-chlorobenzoyl)-4-isopropyl-2(3H)-thiazolone;

5-(4-dimethylaminobenzoyl)-4-methyl-2(3H)-thiazolone;

4-ethyl-5-phenylacetyl-2(3H)-thiazolone;

5-(3 -methoxybenzoyl)-2(3H)-thiazolone;

and 5-[(3,4-dimethylthio)benzoyl]-4-propyl-2(3H)-thiazolone

The formula 1 compounds can be prepared in any manner by standardtechniques analogously known by those skilled in the art. For examplethe formula 1 compounds can be prepared by a Friedel-Crafts acylation ofa thiazolone of formula 3 ##STR3## wherein R₁ is as defined above. Theacylating reagent can be an acid halide of formula 4 ##STR4## wherein R₂is as defined above and X is a bromo group or preferably a chloro group.In addition the acylating reagent of the Friedel-Crafts reaction can bethe free acid or acid anhydride corresponding to the formula 4 acidhalide. Mixed acid anhydrides may also be utilized. The Friedel-Craftsreaction is well known by those skilled in the art and has been reviewedby P. H. Gore in "Friedel-Crafts and Related Reactions", G. A. Olah,editor, Vol. III, Part 1, Interscience Publications, New York, 1964.

The Friedel-Crafts reactions of this invention are performed bypremixing about 1 molar equivalent of the appropriate thiazolone offormula 3 with about 1 molar equivalent to about 10 molar equivalents,preferably about 3 molar equivalents, of a Lewis acid catalyst in asuitable solvent, for example, petroleum ethers; a chlorinated aromatic,such as 1,2,4-trichlorobenzene or dichlorobenzene; or a chlorinatedhydrocarbon, such as carbon tetrachloride, ethylene chloride, methylenechloride, chloroform or preferably tetrachloroethane. about 1 molarequivalent to about 10 molar equivalents, preferably about 1.1. molarequivalents, of the appropriate acid halide of formula 4 is added,preferably dropwise, to the mixture of thiazolone, Lewis acid, andsolvent and the reaction is allowed to proceed for about 1/2 hour toabout 100 hours, preferably from about 1 hour to about 10 hours,depending on the reactants, the solvent, and the temperature which canbe from about -78° to about 150° C., preferably about 0° to about 100°C., most preferably about 60° C. The resulting aroylthiazolone may beisolated from the reaction mixture by any suitable art-known procedure,preferably by quenching the reaction mixture with ice water andsubsequently removing the product by filtration or extraction andsolvent removal or by quenching the cooled reaction mixture withhydrochloric acid and subsequently collecting the solid product byfiltration. Purification can be accomplished by, for example,recrystallization, preferably from ethanol.

Lewis acid catalysts suitable for use in the Friedel-Crafts reactionsdescribed herein are, for example, a metal, such as aluminum, cerium,copper, iron, molybdenum, tungsten, or zinc; a Bronstead acid, such as aphosphoric acid, sulfuric acid, sulfonic acid, or a hydrohalo acid, suchas hydrocloric or hydrobromic acid; halogen substituted acetic acids,such as chloroacetic or trifluoroacetic acids; or a metallic halide,such as a boron halide, zinc chloride, zinc bromide, berryl chloride,copper chloride, iron(III) bromide, iron(III) chloride, mercury(II)chloride, mercury(I) chloride, antimony bromide, antimony chloride,titanium(IV) bromide, titanium(IV) chloride, titanium(III) chloride,aluminum bromide or preferably aluminum chloride.

Alternatively those formula 1 compounds wherein R₂ is a phenyl or benzylsubstituted with a (C₁ -C₄) alkylthio, amino, mono- or di-alkylamino,pyrrolidino, piperidino, morpholino piperazino or N-(C₁ -C₄)alkyl-piperazino can be prepared from the corresponding formula 1compound wherein R₂ is a fluoro substituted phenyl group by an aromaticelectrophilic substitution reaction by conventional techniques.Typically the fluoro substituted compound will be allowed to react withan appropriate thiol or amine at elevated temperature.

Further the formula 1 compounds wherein R₂ is a (C₁ -C₄) alkylsulfinyland (C₁ -C₄) alkylsulfonyl substituted phenyl and benzyl group can beprepared from the corresponding formula 1 compound wherein R₂ is a (C₁-C₄) alkylthio phenyl or benzyl group by simple selective oxidation.Such oxidations can be performed using hydrogen peroxide ormetachloroperbenzoic acid.

The thiazolones of formula 3 are generally available or can be readilyprepared by standard laboratory procedures. For example4-methyl-2(3H)-thiazolone is prepared by reaction of chloroacetone andpotassium thiocyanate in the presence of sodium bicarbonate in aqueoussolution by the procedure of Tcherniac, J. Chem. Soc., 115, 1071 (1919).

The acylating agents of formula 4 are simple derivatives of readilyavailable or preparable benzoic acids and phenylacetic acids. Acidchlorides can be easily prepared from the corresponding carboxylic acidsby treatment with thionyl chloride by techniques well known to thoseskilled in the art.

The compounds of formula 1 are cardiotonic agents useful in thetreatment of heart failure. These compounds can also be used in anyother condition requiring enhanced myocardial contractile force.

The utility of formula 1 compounds as cardiotonics may be determined byadministering the test compound (0.1-100 mg/kg) intravenously,intraperitoneally, intraduodenally or intragastrically in a suitablevehicle to a mongrel dog (either sex). The test dogs are anesthetizedand prepared by isolating a suitable artery (e.g., femoral or commoncarotid) and vein (e.g., femoral or external jugular) introducingpolyethylene catheters filled with 0.1% Heparin-Na to record arterialblood pressure and administer compounds, respectively. The chest isopened by splitting the sternum at the midline or by an incision at theleft fifth intercostal space, and a pericardial cradle is formed tosupport the heart. A Walton-Brodie strain gage is sutured to the rightor left ventricle to monitor myocardial contractile force. Anelectromagentic flow probe may be placed around the root of theascending aorta for measuring cardiac output less coronary blood flow.Heart failure is induced by administering sodium pentobarbital (20 to 40mg/kg) followed by a continuous infusion of 0.25-2 mg/kg/min. orpropranalol hydrochloride (4 mg/kg) followed by a continuous infusion of0.18 mg/kg/min. to the blood perfusing the heart. Followingadministration of either of these cardiac depressants, the right atrialpressure dramatically increases and cardiac output is severelydepressed. Reversal of these effects by the test compound indicatescardiotonic activity.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eithertopically, orally or parenterally, that is, intravenously orintramusuclarly. The amount of compound administered will vary with thepatient, the severity of the cardiac failure and the mode ofadministration.

For topical, oral, or parenteral administration the cardiotonicallyeffective amount of compound and the amount required to enhancemyocardial contractile force is from about 0.1 mg/kg of patients bodyweight per day up to about 400 mg/kg of patient body weight per day andpreferably from about 0.3 mg/kg of patient body weight per day up toabout 120 mg/kg of patient body weight per day.

For oral administration a unit dosage may contain, for example, from 5to 700 mg of the active ingredient, preferably about 15 to 235 mg of theactive ingredient. For parenteral administration a unit dosage maycontain, for example, from 5 to 700 mg of the active ingredient,preferably about 15 to 210. Repetitive daily administration of thecompounds may be desired and will vary with the condition of the patientand the mode of administration.

As used herein, the term "patient" is taken to mean warm bloodedanimals, for example, birds, such as chickens and turkeys, and mammals,such as sheep, horses, bovine cows and bulls, pigs, dogs, cats, rats,mice and primates, including humans.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and an inert filler, such as lactose, sucrose, orcornstarch. In another embodiment the compounds of general formula 1 canbe tableted with conventional tablet bases such as lactose, sucrose orcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compounds in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water, alcohols, oils and otheracceptable organic solvents with or without the addition of a surfactantand other pharmaceutically acceptable adjuvants. Illustrative of oilswhich can be employed in these preparations are those of petroleum,animal, vegetable, or synthetic origin, for example, peanut oil, soybeanoil, and mineral oil. In general, water, saline, aqueous dextrose andrelated sugar solutions, ethanol and glycols such as propylene glycol orpolyethylene glycol, or 2-pyrrolidone are preferred liquid carriers,particularly for injectable solutions.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, a siliconerubber manufactured by the Dow-Corning Corporation.

The following specific examples further illustrate the preparation anduse of the compounds of formula 1 but are not intended to limit thescope of the invention.

EXAMPLE 1 5(4-Fluorobenzoyl)-4-Methyl-2(3H)-Thiazolone

Fluorobenzoyl chloride (25.3 g, 0.16 mol) was added dropwise to amixture of aluminum chloride (60 g, 0.45 mol) and4-methyl-2(3H)-thiazolone (17.3 g, 0.15 mol) in tetrachloroethane (200ml). After the addition was complete, the mixture was stirred for 5hours at 90° C. After the mixture cooled to room temperature, 2Nhydrochloric acid (200 ml) was added dropwise. The resulting precipitatewas collected, washed with water and then with dichloromethane. Thesolid was then dissolved in ethanol and heated with charcoal. Subsequentrecrystallization from ethanol gave the title compound (18.4 g), m.p.209°-210° C.

In a like manner but substituting o-chlorobenzoyl chloride,m-trifluoromethyl or m,p-methylenedioxyphenylacetyl chloride forp-fluorobenzoyl chloride in the above example gives5-(2-chlorobenzoyl)-4-methyl-2(3H)-thiazolone,5-[3-(trifluoromethyl)benzoyl]-4-methyl-2(3H)-thiazolone or5-(3,4-methylene-dioxyphenylacetyl)-4-methyl-2-2(3H)-thiazolone,respectively.

In a like manner but substituting 4-ethyl-2(3H)-thiazolone for4-methyl-2(3H)-thiazolone in the above example gives4-ethyl-5-(4-fluorobenzoyl)-2(3H)-thiazolone.

EXAMPLE 2 5-[4-(dimethylamino)benzoyl]-4-methyl-2(3H)-thiazolone

Dimethylamine (100 ml of 40% solution) was added to a solution of5-(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone. (4.7 g) in ethanol (200ml). The mixture as stirred in a sealed stainless steel vessel at 120°C. for 16 hours. After cooling to ambient temperature the solvent andexcess dimethylamine was evaporated. The residue was recrystallizedtwice from ethanol to give the title compound mp. 224°-226° C.

In a like manner but substituting pyrrolidine, morpholine or1-methylpiperazine for the dimethylamine in the above example gives

5-[4-(pyrrolidino)benzoyl]-4-methyl-2(3H)-thiazolone,

5-[4-(morpholino)benzoyl]-4-methyl-2(3H)-thiazolones

or 5-[4-(4-methylpiperazino)benzoyl]-4-methyl-2(3H)-thiazolone.

EXAMPLE 3 4-Methyl-5-[4-(Methylthio)benzoyl]-2(3H)-Thiazolone

Gaseous methylmercaptan is added to a solution of5(4-fluorobenzoyl)-4-methyl-2(3H)-thiazolone (4.7 g) in ethanol (200 ml)to saturation. The mixture is heated at 120° C. in a sealed stainlesssteel container for 16 hours. After cooling to ambient temperature, themixture is evaporated to dryness. The residue is recrystallized twicefrom ethanol to give the title compound.

Substituting 1-butanethiol for methyl mercaptan gives5-[4-(butylthio)benzoyl]-2(3H)-thiazolone.

EXAMPLE 4 4-Methyl-5-[4-(Methylsulfinyl)benzoyl]-2(3H)Thiazolone

Hydrogen peroxide (1 equivalent, 30%) is added to a solution of4-methyl-5-[4-(methylthio)benzoyl]-2(3H)-thiazolone (2.7 g) in glacialacetic acid (80 ml). The mixture is stirred for 3 hours at 50° C. Theprecipitate obtained on addition of water is recrystallized from ethanolto give the title compound.

Using 2.5 equivalents of hydrogen peroxide and extending the reactiontime to 16 hours at 50° C. gives 4-methyl-5-[4-(methylsulfonyl)benzoyl]-2(3H)-thiazolone.

EXAMPLE 5

A tablet is prepared from

5-(4-dimethylaminobenzoyl)-4-methyl-2(3H)-thiazolone: 250 mg

Starch: 40 mg

Talc: 10 mg

Magnesium: 10 mg

EXAMPLE 6

A capsule is prepared from

4-ethyl-5-phenylacetyl-2(3H)-thiazolone: 400 mg

Talc: 40 mg

Sodium Carboxymethylcellulose: 40 mg

Starch: 120 mg

What we claim is:
 1. A compound of the formula ##STR5## wherein R₁ is ahydrogen or (C₁ -C₄) alkyl group, andR₂ is an unsubstituted benzyl or aphenyl or benzyl substituted with one or two members of the groupconsisting of (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy, carboxy, carb(C₁ ₁-C₄)alkoxy, imidazolyl, (C₁ -C₄) alkylthio, (C₁ -C₄) alkylsulfinyl, (C₁-C₄) alkylsulfonyl, trifluoromethyl, cyano, amino, mono- and di- (C₁ C₄)alkylamino, pyrrolidino, piperidino, morpholino, piperazino N-(C₁ -C₄)alkyl-piperazino or halogen group or a methylenedioxy group.
 2. Acompound of claim 1 wherein R₁ is a hydrogen, methyl, or ethyl group. 3.A compound of claim 1 wherein R₂ is a substituted phenyl group.
 4. Acompound of claim 2 wherein R₂ is a substituted phenyl group.
 5. Acompound of claim 1 wherein R₂ is a phenyl substituted with an amino ora mono- or di- (C₁ -C₄) alkylamino group.
 6. A compound of claim 2wherein R₂ is a phenyl substituted with an amino or a mono- or di- (C₁-C₄) alkylamino group.
 7. A compound of claim 1 wherein R₂ is adimethylaminophenyl group.
 8. A compound of claim 2 wherein R₂ is adimethylaminophenyl group.
 9. A compound of claim 1 wherein R₁ is amethyl group and R₂ is a dimethylaminophenyl group.